PROJECT SUMMARY: Brain represents the organ with luxurious vascular-rich microenvironment. Glioblastoma (GBM) appears to take the advantage of this vascular-rich microenvironment for its rapid growth. Nonetheless, rapid expansion of the tumor causes the change of microenvironment, specifically in the tumor core, creating the subsequent hypovascular and hypoxic condition. On the other hand, tumor cells in the leading edge remain surrounded by enriched vasculature. Recent studies including ours have shown the cellular and molecular heterogeneity between the tumor core and edge. This notion has raised a possibility that we may need to develop distinct therapies for the tumor cells located in the core and edge. Given that surgery can remove most of the tumor core, it is likely that tumor cells located in the leading edge may contain seeds for recurrence to create the core in recurrent tumors. Of note, the majority of GBM patients die due to tumor recurrence but not due to the initial nave tumors. Therefore, it is critically important to characterize the tumor cells in the leading edge that are tightly surrounded by the normal brain tissues including the rich vasculature. This proposal will seek to determine the molecular mechanisms to control edge- and core-tumor cells so that we can eventually develop novel therapies to block the tumor recurrence from the edge cells. In Aim 1, we will molecularly characterize the persistent phenotype of edge-tumor cells in GBMs that are tightly associated with brain vasculature. In Aim 2, we will investigate the post-therapeutic transition of edge-tumor cells to develop their derivative tumor core. In Aim 3, we will perform pre-clinical therapeutic efficacy tests to target both the edge- and core-tumor cells. In all Aims, we will use both mouse and human GBM models derived from tumor core and tumor edge. These models, when combined, faithfully recapitulate GBM-like tumors in mouse brains holding both tumor core lesion and edge lesion with distinct molecular profiles. When completed, we believe that this proposal will provide novel insights on the molecular mechanisms to differentially regulate tumor edge and tumor core.